Memorandum

Islet Sciences and BHV Pharma announce positive topline phase 2b results on SGLT-2 inhibitor remogliflozin etabonate – April 16, 2014

Executive Highlights

  • In treatment-naïve patients, twice-daily SGLT-2 inhibitor remogliflozin etabonate yielded A1c reductions of 1.0-1.4% and weight loss of 3-8 lbs, but also an increase in LDL and genital mycotic infections; once-daily administration yielded less efficacy, fewer side effects.
  • Based on these results, Islet Sciences and BHV Pharma have developed a once-daily bi-phasic formulation that they expect to maintain the efficacy of twice-daily dosing but provide improved safety/tolerability.
  • As a reminder, Islet Sciences recently acquired BHV Pharma.

Earlier today, Islet Sciences and BHV Pharma announced positive results from two 12-week placebo and pioglitazone-controlled randomized phase 2b studies investigating the SGLT-2 inhibitor remogliflozin etabonate in treatment-naïve type 2 diabetes patients. One study tested a once-daily dose of the drug, while the other tested a twice-daily dose. Twice-daily administration led to generally better A1c-lowering efficacy (1.0-1.4%; no baseline provided; p<0.001 compared to baseline) and better weight loss (1.36-3.51 kg or ~3-8 lbs across treatment arms from baseline) but an increase in LDL cholesterol and genital mycotic infections “similar to what has been demonstrated with other SGLT-2 inhibitors.” In contrast, once-daily administration led to more modest A1c lowering (0.5-0.8%; no baseline provided; p<0.047 compared to baseline) and weight loss (1.44-1.51 kg or ~3 lbs across treatment groups from  baseline) but a lower incidence of genital mycotic infections and generally no increases in LDL. Both doses led to statistically significant decreases in fasting plasma glucose from baseline (no specific figures provided). According to the companies, the better efficacy and worse side effects associated with the twice-daily regimen are due to the longer duration of plasma drug exposure during the evening meal and during sleep. The companies expect to present full phase 2b results at ADA 2014.

Following the results from these two trials, Islet Sciences and BHV Pharma have developed a once-daily bi-phasic formulation (a drug that has two peaks) of remogliflozin etabonate that they expect to maintain the efficacy of the twice-daily dose while providing an improved side effect profile that more mimics that of the once-daily dose. The company informed us that this new formulation has successfully completed a phase 1 study and will be tested in a phase 2b study prior to moving on to phase 3. This wait might be worth it if modulating the release of the drug in a bi-phasic manner yields a reduction in the SGLT-2 inhibitor class’ two biggest safety/tolerability concerns (genital mycotic infections and an increase in LDL). It is difficult to read too far into the phase 2b results without knowing the sample size and the comparisons to placebo and pioglitazone results, but the bi-phasic formulation could offer remogliflozin etabonate real potential for differentiation against a growing SGLT-2 inhibitor competitive landscape and it was a positive to hear about this. Furthermore, in October 2013, BHV Pharma announced phase 2 results indicating that the candidate maintained its PK/PD profile in patients with mild or moderate renal impairment (see item #4 of our October 16, 2013 Letter); if confirmed in further testing, this effect would provide the drug with a comparative advantage against J&J’s Invokana (canagliflozin) and AZ’s Farxiga (dapagliflozin), which are either contraindicated or require dose adjustment in patients with moderate renal impairment.

As background, Islet Sciences is focused on developing type 1 diabetes therapies utilizing encapsulated islet cell transplantation. Last month, the company announced its acquisition of BHV Pharma (the owner of remogliflozin etabonate along with Kissei) with an upfront payment of ~$12 million in stock – read our report

  • The bi-phasic formulation of remogliflozin etabonate would aim to reduce the side effects associated with SGLT-2 inhibition by avoiding nocturnal SGLT-2 inhibition. Islet CEO Dr. James Green believes that nocturnal SGLT-2 inhibition is the underlying culprit for why the drug class is associated with genitourinary infections and LDL cholesterol increases. Dr. Green stated that nocturnal SGLT-2 inhibition, specifically during sleep, is connected with genitourinary infections because patients will accumulate glucose in the bladder (along with water due to osmotic diuresis). This causes mild incontinence and nocturnal urination, which provides a rich environment for microbial growth. SGLT-2 inhibition during the daytime poses less of a risk for infection because people ingest water more frequently during the day, allowing for more frequent urination and more diluted glucose concentration in the bladder. We hadn’t heard this explanation before and found it of interest. Dr. Green also indicated that Islet’s data suggests that nocturnal inhibition of SGLT-2 inhibition is also responsible for SGLT-2 inhibitors’ effect on increasing LDL cholesterol due to perturbations in glucose and lipid metabolism in the “fasting” state at night.

-- by Manu Venkat, Jessica Dong, and Kelly Close